title: The heart of the matter: protection of the myocardium from T cells.
abstract: Myocardial inflammation and damage can lead to lethal acute or chronic cardiac failure. A variety of regulatory mechanisms limit the magnitude and duration of T cell responses in the heart. Insights into these regulatory mechanisms have come from studies of specific deficiencies in central or peripheral T cell tolerance which cause or enhance the severity of myocarditis. Under non-inflammatory conditions, constitutive DC presentation of cardiac peptides to naïve T cells in cardiac draining lymph nodes tolerizes recirculating naïve T cells specific for these antigens. Cardiac antigen-specific naïve T cells, especially those specific of α-myosin heavy chain peptides, become activated and differentiate into expanded clones of effector T cells under various conditions, such as cardiac infection and/or genetic variations in peripheral tolerance. The pathology that these effector cells cause in the myocardium is limited by PD-L1 expressed on myocardial cells in response to inflammatory cytokines, and by CTLA-4 dependent mechanisms. The PD-1:PD-L1 pathway works together with other control mechanisms to keep the heart safe from T cells, and combined impairment of this pathway along with other regulatory mechanisms synergize to cause myocarditis. T cell derived IFNγ contributes to the inflammatory damage to the heart in autoimmune myocarditis, but it also engages regulatory mechanisms that limit disease, including upregulation of PD-L1, and differentiation of TNF and iNOS expressing DCs from monocytes. iNOS derived from these DCs and other IFNγ stimulated cells inhibits expansion of T cells that cause myocarditis. Regulatory T cells also appear to be critical for suppression of effector T cells specific for myocardial antigens.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, NRB Room 752N, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: alichtman@partners.org.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Lichtman
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D060890:B7-H1 Antigen / Q000378:metabolism; D024722:Cardiac Myosins / Q000276:immunology; D006333:Heart Failure / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000276:immunology*; D051379:Mice; D009205:Myocarditis / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001324:Autoantigens; D060890:B7-H1 Antigen; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D024722:Cardiac Myosins
keywords: Autoimmunity; Heart; Myocarditis; Myosin; T cells; Tolerance